Adult stem cells maintain tissue homeostasis and regeneration throughout the animal's lifetime. The murine hair follicle offers a model system for studying the mechanism of tissue regeneration. The hair follicle consists of three regions: the lower segment (bulb), the middle segment (bulge and isthmus), and the upper segment (infundibulum). After initial morphogenesis, the lower segment of hair follicles undergo repeated cycles of catagen (regression phase), telogen (resting phase), and anagen (proliferation phase). Underpinning this regenerative cycle is the multi-potent and self-renewal capability of hair follicle stem cells (HFSCs), which reside in a specialized niche called the bulge.
In telogen, both bulge stem cells (Bu-SCs) and secondary hair germ (Hg), a small cluster of cells beneath the bulge, are quiescent. Hg directly adjoins a population of mesenchymal cells, called the dermal papillae (DP). At anagen onset, Hg becomes activated prior to Bu-SCs by responding to cues from the DP and surrounding microenvironment. Proliferative Hg then generates the hair matrix, the transit-amplifying cells (TACs) of hair follicles, which has distinct molecular signatures from that of Bu-SCs/Hg. Matrix cells proliferate and progress to differentiate into the hair shaft and inner root sheath (IRS) during anagen. In contrast to Hg, Bu-SCs become activated 1-2 days later in anagen to make the extending outer root sheath (ORS) and to self-renew briefly for replenishing the expended HFSCs. In catagen, the hair progeny (matrix, lower ORS) apoptoseses and the remaining epithelial strand retracts upward together with the DP. At catagen/telogen transition, some upper ORS cells that survive catagen form the new bulge and hair germ being used for the next hair cycle.
In mammals, four Notch receptors (Notch1-4) and five canonical Notch ligands (Jagged1-2, Delta1, 3, and 4) have been identified. Notch ligand-receptor interactions between contacting cells lead to serial proteolysis of the Notch receptor to generate Notch intracellular domain (NICD). NICD translocates into the nucleus and binds to Rbpj and Mastermind, thereby activating the downstream effectors, including the Hes and Hey gene family of transcriptional repressors. Notch signaling is modulated by glycosylation of the extracellular domain of Notch receptors. One of the modifiers is protein O-fucosyltransferase 1 (Pofut1), which transfers O-fucose to a particular consensus sequence in the EGF-like repeats of Notch receptor extracellular domain and is ubiquitously expressed in mammalian tissues. Biochemical studies demonstrated that O-fucose modification of mammalian Notch receptors is required for efficient ligand-receptor binding and subsequent signal transduction. Loss of Pofut1 in the mouse embryo resulted in a severe phenotype similar to that of embryos lacking core components of Notch signaling pathway, such as Presenilins and Rbpj.
Expression patterns of Notch ligands, receptors, and downstream effectors in embryonic and adult skin are in a complex and dynamic manner (Watt F M et al., Curr Opin Cell Biol 20:171-179, 2008). Loss and gain-of-function animal studies revealed that canonical Notch-Rbpj signaling axis acts as a commitment switch at the basal/spinous layer (Blanpain C et al., Genes Dev 20:3022-3035, 2006). Loss of Notch signaling does not affect hair follicle patterning or hair placode formation; however, Notch signaling is required for complete differentiation of the hair follicle (Blanpain C et al., Genes Dev 20:3022-3035, 2006). Interestingly, epithelial deletion of Notch1 or Notch ligand Delta1 caused defects in anagen phase of the first hair cycle, suggesting that Notch signaling may play a role in the hair cycle regulation.
The basic helix-loop-helix (bHLH) gene Hes1 is an important effector mediating context-dependent function of Notch signaling in a variety of tissue types. Hes1 has been involved in the maintenance of stem/progenitors cells in nervous and digestive system by negatively regulating tissue-specific bHLH activators. Moreover, Hes1 is expressed in the spinous keratinocytes and required for maintaining the progenitor fate of spinous cells via regulating Ascl2, a bHLH transcriptional activator, during epidermal development. Interestingly, Hes1-null epidermis developed normally when transplanted to adult mice, suggesting a restricted role of Hes1 in developmental stages. Hes1 is expressed at low levels in telogen hair follicles, and its expression is increased in growing hair follicles. However, the exact function of Hes1 in the hair cycle and its role in the maintenance of the hair follicle stem/progenitor cells are less understood.